Clinical Review & Education

JAMA Psychiatry | Special Communication

Bridging Knowledge Gaps in the Diagnosis and Management

of Neuropsychiatric Sequelae of COVID-19
Jennifer A. Frontera, MD; Naomi M. Simon, MD, MSc

IMPORTANCE Neuropsychiatric symptoms have been reported as a prominent feature of

postacute sequelae of COVID-19 (PASC), with common symptoms that include cognitive
impairment, sleep difficulties, depression, posttraumatic stress, and substance use disorders. A
primary challenge of parsing PASC epidemiology and pathophysiology is the lack of a standard
definition of the syndrome, and little is known regarding mechanisms of neuropsychiatric PASC.

OBSERVATIONS Rates of symptom prevalence vary, but at least 1 PASC neuropsychiatric

symptom has been reported in as many as 90% of patients 6 months after COVID-19
hospitalization and in approximately 25% of nonhospitalized adults with COVID-19. Mechanisms
of neuropsychiatric sequelae of COVID-19 are still being elucidated. They may include static brain
injury accrued during acute COVID-19, neurodegeneration triggered by secondary effects of
acute COVID-19, autoimmune mechanisms with chronic inflammation, viral persistence in tissue
reservoirs, or reactivation of other latent viruses. Despite rapidly emerging data, many gaps in
knowledge persist related to the variable definitions of PASC, lack of standardized phenotyping
or biomarkers, variability in virus genotypes, ascertainment biases, and limited accounting for
social determinants of health and pandemic-related stressors.

CONCLUSIONS AND RELEVANCE Growing data support a high prevalence of PASC Author Affiliations: Department of
neuropsychiatric symptoms, but the current literature is heterogeneous with variable Neurology, New York University
Grossman School of Medicine, New
assessments of critical epidemiological factors. By enrolling large patient samples and
York (Frontera); Department of
conducting state-of-the-art assessments, the Researching COVID to Enhance Recovery Psychiatry, New York University
(RECOVER), a multicenter research initiative funded by the National Institutes of Health, will Grossman School of Medicine, New
help clarify PASC epidemiology, pathophysiology, and mechanisms of injury, as well as York (Simon).
identify targets for therapeutic intervention. Corresponding Author: Naomi M.
Simon, MD, MSc, Department of
Psychiatry, NYU Grossman School of
JAMA Psychiatry. 2022;79(8):811-817. doi:10.1001/jamapsychiatry.2022.1616 Medicine, One Park Avenue, 8th
Published online June 29, 2022. Floor, New York, NY 10016 (naomi.
simon@nyulangone.org).

T
his Special Communication highlights what is currently un-
derstood about neurological and psychiatric (herein neu-
ropsychiatric) symptoms in adults that develop and per-
sist after SARS-CoV-2 infection and considers them in the context
of the pandemic using a targeted rapid review of the literature.
We then introduce Researching COVID to Enhance Recovery
(RECOVER), 1 a multicenter research initiative funded by the
National Institutes of Health (NIH) to help identify and address the
postacute sequelae of COVID-19 (PASC).
A primary challenge of parsing PASC epidemiology and patho-
physiology is the lack of a standardized and biologically based defini-
tion of the syndrome. While the Centers for Disease Control and Pre-
vention (CDC) describes post–COVID-19 conditions as occurring 4
weeks or more after infection,2 the World Health Organization (WHO)
definition3 requires symptoms to be present 3 months or longer after
infection and to last 2 months or longer. Because the WHO definition
was released October 6, 2021, most publications use heterogeneous
time frames, in part because authors used pragmatic definitions prior
to the CDC or WHO guidance statements. Other groups have also
published PASC definition guidelines. The UK National Institute for
Health and Care Excellence (NICE) put forth 2 definitions of PASC:
(1) ongoing symptomatic COVID-19 lasting 4 to 12 weeks after the on-
setofacutesymptomsand(2)post–COVID-19syndromeforthosewith
symptoms longer than 12 weeks after the onset of acute COVID-19.4
For the purposes of this communication, we use the CDC definition of
symptoms occurring 4 weeks or longer from index infection.
Methods
We conducted a targeted rapid review of literature published on
PubMed and PsycInfo between January 2020 and February 1, 2022,
using the search terms “chronic COVID,” “post-acute COVID,” “Long-
Haul Covid,” “Long-Hauler Covid,” “Long Covid,” “post-acute se-
quelae,” “persistent symptom,” “SARS-CoV-2,” AND “psychiatric” OR
“psychological” OR “neurological” OR “neuropsychiatric” OR “mental
disorders” OR “depression” OR “anxiety” OR “cognition” or “mood dis-
orders” OR “brain.” Relevant articles were reviewed by both authors
for inclusion. In this rapid review, we used transparent and reproduc-
ible search methods; however, because of time contraints and the rap-
idly changing nature of COVID-19 literature, source searches were lim-
ited in scope. In addition, we did not include a risk-of-bias assessment,

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 Clinical Review & Education Special Communication
an analysis of missing data or data heterogeneity, a meta-analysis, or
a certainty assessment, as are typical in a formal systematic review.
Epidemiology
Acute Neuropsychiatric Symptoms
(<4 Weeks From SARS-CoV-2 Infection)
Acute COVID-19 neuropsychiatric symptoms may persist in a sub-
set of patients or recur later, consistent with PASC. Understanding
the continuity of symptoms from the acute to postacute period is
critical to identifying risk factors and mechanisms underlying PASC.
For example, some symptoms may represent a static insult with re-
sidual disability (eg, stroke), while others may represent ongoing mal-
adaptive responses, such as inflammation or autoimmune mecha-
nisms. Other symptoms may be tied to acute illness factors but wane
over time. Disaggregating etiologies hinges on evaluating the en-
tire disease course from the acute to postacute periods as well as
contextualizing symptoms in the evolving pandemic environment.
The overall prevalence of neuropsychiatric symptoms during
acute COVID-19 is difficult to estimate, and differences among SARS-
CoV-2 variants are still emerging. Because at least 33% of individu-
als infected with SARS-CoV-2 are completely asymptomatic during
the acute phase of infection, the association between SARS-CoV-2
and neuropsychiatric symptoms may be unrecognized, potentially
leading to underestimates of PASC after asymptomatic or mild
COVID-19.5 Conversely, acute neurological events among hospital-
ized patients with severe COVID-19 are extensively documented,
with prevalence rates from 14% to 33%6,7 across heterogeneous
studies. The most prevalent reported neurologic symptoms are fa-
tigue in 33%,8 sleep abnormalities in 29%,9 headache in 23%,10 and
anosmia/dysgeusia in 18%.7 Meta-analyses addressing psychiatric
symptoms have reported pooled prevalence rates as high as 42%
to 45% for depression and 37% to 47% for anxiety,9,11 both higher
than rates without infection (eg, 24% depression, 26% anxiety)
(Table 1).6-22 Although control groups are variably included, some
studies suggest higher rates of ischemic stroke, hemorrhagic stroke,
Guillain-Barré syndrome, neuropathy, myopathy or neuromuscu-
lar junction disorder, anxiety, mood disorder, psychotic disorder, in-
somnia, and substance abuse disorder compared with patients with
influenza or other respiratory tract infections.16,23
Postacute Neurological Events and Psychiatric Symptoms
(≥4 Weeks From SARS-CoV-2 Infection)
Post–COVID-19 neuropsychiatric sequelae have been reported in up to
91% of patients with COVID-1914 6 months after hospitalization and in
approximately 25% of nonhospitalized individuals with COVID-19.12
However, sequelae rates vary depending on the spectrum of compli-
cations considered, the severity of the index infection and course, the
time window from initial infection, and the assessment methodology.
The most commonly reported post–COVID-19 neuropsychiatric events
occurring within 4 weeks to 6 months postinfection include cognitive
abnormalities(4%-47%),12,14,15,19,20 sleepdisturbances(3%-27%),12,14,16
anxiety (7%-46%),12-14,24 depression (3%-20%),12-14,24 posttraumatic
stress disorder (PTSD) (6%-43%),13,24 fatigue (5%-32%),12,14,15,17 and
headache (5%-12%)12,15 (Table 1). These rates appear to be higher than
ratesobservedinsimilarpatientpopulationswithoutCOVID-19.Among
73 000 nonhospitalized patients 30 days or longer after infection,
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Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19
incident onset of anxiety and fear-related disorders and trauma- and
stress-relateddisorderswassignificantlygreaterthanamongthosewith-
out COVID-19.25 Additionally, rates of stroke, dementia, mood, anxiety,
psychotic, and substance use disorders were each significantly higher
at 6 months than among control patients with influenza or other respi-
ratoryconditions(Table1).15 However,notallstudieshavefoundhigher
rates of mood and anxiety symptoms after COVID-19 hospitalization
thanamongcomparatorgroups,andsubstantialvariabilityexistsinstudy
methodsandquality.26 Studieswithshortertimeframes(eg,1-3months)
tendtoreporthigherthresholdanxiety,depression,andPTSDratesthan
those more than 3 months postinfection, although early distress (eg,
at 1 month) predicts 1-year depression, anxiety, and traumatic distress,
irrespectiveofpriorpsychiatrichistoryorgender,27 supportingtheneed
for longitudinal studies. That prior neuropsychiatric illness is also asso-
ciated with higher rates of hospitalization, intensive care unit (ICU)
admission,andmortalitywithCOVID-1916,28 highlightsthepotentialfor
bidirectional risk.
Risk Factors for Neuropsychiatric PASC
Systematicresearchisneededtobetterunderstandriskfactorsforneu-
ropsychiatric aspects of PASC. Individuals with preexisting neurologi-
cal or psychiatric histories are at risk for worsening and/or recurrence
withCOVID-19.6 Althoughdataareinconsistent,moresevereCOVID-19
disease and course (requirement of hospitalization, use of invasive
mechanical ventilation, and/or ICU admission) are risk factors for
PASC.15,16,25 Multiomics analyses suggest that history of diabetes, ini-
tial SARS-CoV-2 viral load, autoantibodies (anti-interferon and anti-
nuclear), and reactivation of latent Epstein-Barr virus at COVID-19
illness onset may all predict PASC.29 Of note, risk factors for neuro-
psychiatric events that occur acutely after COVID-19 (older age, male
sex, White race, COVID-19 illness severity, medical comorbidities, and
past neurological and psychiatric disease)14 vary substantially from risk
factors for postacute neuropsychiatric sequelae (middle age, female
sex, racial and ethnic minority groups, baseline disability, fewer years
of formal education, and/or a history of psychiatric disease).14,30 Po-
tential hypotheses include that mechanisms of injury more common
in middle-aged women, such as autoimmune disease, may explain
some of these differences. Social determinants of health, variability in
access to health care, and community-specific stigma surrounding
treatment of psychiatric illness that may include physical symptom-
atology may also contribute.
Mechanisms of Injury
Acute Phase
The preponderance of human data suggests the pathophysiology un-
derpinning neuropsychiatric injury during acute infection is related to
secondary effects of SARS-CoV-2, including hypoxemia, hyperinflam-
mation, and hypercoagulability. Neuropathological evidence of acute
hypoxic-ischemic brain injury exists in multiple COVID-19 autopsy
cohorts.31 Additionally, elevations in proinflammatory cytokines, par-
ticularly IL-6, is a hallmark of moderate-severe acute COVID-19 known
to promote endothelial dysfunction, vascular permeability, and po-
tentially blood-brain barrier (BBB) dysfunction.32 Neuropathological
data among COVID-19 decedents have revealed endothelial injury,
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 Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19 Special Communication Clinical Review & Education

Table 1. Prevalence of Neuropsychiatric Events in the Acute (≤4 Weeks) and Postacute (>4 Weeks, >3-6 Months) Periods After COVID-19
Based on a Targeted Rapid Literature Review

Event type Acute prevalence Postacute prevalence Comment

Depression Hospitalized 48%9 >4 wk Post 11%-20%12,13 Based on pooled prevalence, primarily from symptom
COVID-19 surveys rather than structured psychiatric interview
Nonhospitalized 35%9 >3-6 mo Post 3%-16%14,15 Surveys or ICD codes
COVID-19
Anxiety Hospitalized 42%9 >4 wk Post 13%-30%12,13 Based on pooled prevalence, primarily from symptom
COVID-19 surveys rather than structured psychiatric interview
9 14,16,17
Nonhospitalized 33% >3-6 mo Post 7%-46% Surveys or ICD codes, meta-analysis
COVID-19
6
Cognition Hospitalized 7%, >4 wk Post 12%-33%,12-14 Acute toxic-metabolic encephalopathy excludes
Toxic-metabolic COVID-19 Subjective and patients with mental status changes due to sedation
encephalopathy objective cognitive medications; postacute includes symptom surveys,
abnormalities cognitive testing
Hospitalized, 55%,18 Delirium >3-6 mo Post 4%-47%,14,15,19,20 Acute delirium includes mental status changes related
intensive care COVID-19 Subjective and to sedation; postacute includes symptom surveys,
unit objective cognitive cognitive testing
abnormalities
Fatigue Hospitalized and 32%7,8 >4 wk Post 11%12 Postexertional fatigue described
nonhospitalized COVID-19
>3-6 mo Post 5%-32%14,15,17 Symptom questionnaires and meta-analysis
COVID-19
9 12,13
Sleep Hospitalized 29% >4 wk Post 8%-27% Most data from symptom surveys rather than formal
disturbance COVID-19 sleep studies
14,16
>3-6 mo Post 3%-10%
COVID-19
Headache Nonhospitalized 13%-23%7,10 >4 wk Post 9%-12%12,13 Most often bilateral, pressing quality; may have
COVID-19 migrainous features, chronic daily headache as well
>3-6 mo Post 5%15
COVID-19
Anosmia, Hospitalized and 11%-18%7,13 >4 wk Post 5%12 Likely olfactory epithelium and support cell injury,
dysgeusia nonhospitalized COVID-19 rather than olfactory nerve injury; less common with
omicron variant
Ischemic stroke Hospitalized 1%-2%6,7 NA NA Occurs at higher rates than following influenza; more
often cryptogenic etiology
Intracerebral Hospitalized 0.4%6 NA NA Anticoagulation is a major risk factor; may occur in
hemorrhage unusual patterns at gray white junction, can be
multifocal and multicompartmental
Subarachnoid Hospitalized 0.1%6 NA NA Spontaneous or aneurysmal
hemorrhage
21
Cerebral venous Hospitalized 0.1% NA NA Associated with hypercoagulable and
thrombosis hyperinflammatory state of COVID-19
Seizure Hospitalized 2%6 NA NA Can be new onset or worsening of underlying epilepsy;
status epilepticus has been reported
Movement Hospitalized 1%6 NA NA Generalized myoclonus, tremor reported
disorder
6
Guillain-Barré Hospitalized 0.1% NA NA Most commonly diagnosed as acute axonal or
syndrome demyelinating acute inflammatory polyneuropathy;
other variants, such as Miller Fisher syndrome,
pharyngeal-cervical-brachial, and polyneuritis cranialis
have been described
Bell palsy Nonhospitalized 0.1%22 NA NA Other cranial neuropathies reported, including
oculomotor, vagus, accessory, hypoglossal
Posttraumatic NA NA >4 wk Post 6%-43%13 Primarily self-report screeners reported
stress COVID-19
Psychosis NA NA ≤6 mo Post 1.4% prevalence, ICD codes; higher with hospitalization
COVID-19 0.4% new16
Substance use NA NA ≤6 mo Post 7% prevalence, ICD codes; higher with hospitalization
disorder COVID-19 2% new16
Vision NA NA >4 wk Post 7%12 Based on symptom questionnaires, not objective testing
abnormalities COVID-19
Dizziness, NA NA >4 wk Post 7%12 May be associated with postural hypotension
lightheadedness COVID-19

Abbreviations: ICD, International Classification of Diseases; NA, not applicable.

microhemorrhages, disruption of the microvasculature basal lamina,
and extravasation of fibrinogen into brain parenchyma,33 all sugges-
tive of BBB disruption that may be mediated by a COVID-19–related
inflammatory state. Intense inflammation in turn triggers hyperco-
agulability resulting in microthromboses and microvascular endothe-
lial injury, seen in postmortem neuropathological studies.31 Hyperco-
agulability coupled with endothelial injury may lead to ischemic stroke,
hemorrhagic conversion, or primary intracranial hemorrhage.34 Neu-
rodegenerative blood markers (GFAP, NFL, UCHL1) indicating injury to
neurons, glia, and axons are acutely elevated in hospitalized patients
with COVID-19 (and no history of neurodegenerative disease) to lev-
els observed in control patients with Alzheimer disease but without
COVID-19, particularly among patients with acute neurological symp-
toms, suggesting profound brain injury for some.35

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 Clinical Review & Education Special Communication
While direct neuronal invasion by the SARS-CoV-2 virus has been
postulated as a mechanism of injury, most neuropathological evi-
dence suggests it is not a driving factor. While SARS-CoV-2 RNA has
been identified by polymerase chain reaction in regionally based
samples of olfactory mucosa and surrounding tissue, in situ hybridiza-
tion (more cell specific and less prone to contamination by neighbor-
ingcells)didnotdetectSARS-CoV-2inanyneuraltissuein2studies.36,37
Most other reports of SARS-CoV-2 detection by reverse transcriptase–
polymerase chain reaction in neural tissue either did not report levels
or had low RNA copies,31 which may represent contamination.38
Postacute Phase
Little is known regarding mechanisms of neuropsychiatric PASC, and
it is likely that host, viral, and environmental factors contribute to
differing degrees depending on the PASC subphenotype. Here we
present several hypothetical mechanisms of PASC. First, PASC symp-
toms may represent static brain injury accrued during acute COVID-
19. Patients with COVID-19–related ischemic stroke, intracranial hem-
orrhage, or hypoxic-ischemic brain injury may have trajectories of
recovery that span months to years, and many may have perma-
nent disabilities. Additionally, critical illness of any cause is associ-
ated with long-term cognitive deficits39 as well as motor deficits re-
lated to critical illness neuropathy/myopathy. In these cases, disability
is largely related to secondary complications of COVID-19, rather than
an ongoing insult specific to SARS-CoV-2.
Another mechanism may involve progressive neurodegenera-
tion triggered by post–COVID-19 hypoxia, inflammation, and BBB dis-
ruption, similar to that described in other disease models, such as
traumatic brain injury. Hypoxia, particularly chronic hypoxia, has been
linked to early Alzheimer disease pathology by a variety of mecha-
nisms that lead to amyloid β accumulation,40 with decreased amy-
loid breakdown. Neuroinflammation may additionally promote both
amyloid plaque and neurofibrillary tangle formation.41 Other neu-
rodegenerative diseases, such as Parkinson, may occur or progress
at higher rates after SARS-CoV-2 infection.42
Autoimmune mechanisms for neuropsychiatric PASC have also
been proposed. Indeed, acute disseminated encephalomyelitis, acute
necrotizing encephalomyelitis, Guillain-Barré syndrome, and trans-
verse myelitis, which are believed to be caused by molecular mimicry,
have all been reported after SARS-COV-2 infection, although onset is
typically within 7 to 14 days (Table 1). Autoantibodies, including anti-
interferon α2 and antinuclear antibodies, have been correlated with
postacute respiratory and gastrointestinal symptoms.29 A compart-
mentalized central nervous system autoimmune response following
SARS-CoV-2 infection has also been observed, further bolstering this
hypothesis.43 Some data suggest these autoantibodies precede
COVID-19 and only generate clinical syndromes following SARS-
CoV-2 infection.29 Notably, PASC shares some symptomatic similari-
ties with chronic fatigue syndrome, which may have autoimmune un-
derpinnings, such as autoantibodies to neurotransmitters, changes in
cytokine profiles, and decreased natural killer cell cytotoxicity.44 Ad-
ditionally, there has been an increase in diagnoses of chronic fatigue
syndrome 3 to 9 months after SARS-CoV-2 infection among nonhos-
pitalized patients.45
Viral persistence in immune sanctuaries has been postulated as
a PASC mechanism, similar to that described with HIV; this specu-
lation is largely driven by cases of persistent viral shedding in im-
munosuppressed patients.46 Alternately, reactivation of latent
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Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19
viruses may occur, such as herpesviruses (herpes simplex virus 1, vari-
cella zoster, Epstein-Barr). Initial SARS-CoV-2 viral load and Epstein-
Barr viremia during acute COVID-19 have been implicated in post-
acute memory concerns.29
Both autoimmunity and viral persistence can contribute to per-
sistent chronic inflammation in patients with PASC.47 Persistence of
proinflammatory cells, altered cytokine production, and immune-
metabolic pathway disruptions may all play a role in promoting a
chronic inflammatory state.47 Furthermore, persistent inflamma-
tory responses such as IL-6 cytokine dysregulation have been re-
ported, consistent with decades of psychoneuroimmunology re-
search in patients with anxiety disorders, depression, and traumatic
stress–related disorders.27,48 Complex interactions between preex-
isting psychiatric disease, psychiatric medications, stress, and SARS-
CoV-2 infection effects on inflammation and neuronal function have
been highlighted as needing further study.49 For example, treat-
ment with serotonin selective reuptake inhibitors, fluoxetine or
fluvoxamine in particular, may be acutely protective against COVID-
19–related mortality, with mechanistic hypotheses including re-
duced inflammation, decreased platelet aggregation, and func-
tional inhibition of acid sphingomyelinase.50
While ongoing research efforts are beginning to help elucidate
the COVID-19–related biological underpinnings such as immune-
inflammatory dysregulation27 across the range of neuropsychiatric
PASC symptoms and severity, it should be noted that environmen-
tal factors, including stressors, social determinants of health, and re-
siliency factors, likely also contribute to the aforementioned mecha-
nisms of PASC. For example, pandemic-related stressors have been
shown to affect such symptoms as cognition, anxiety, depression,
fatigue, and sleep and may play a larger role in generating these
symptoms than SARS-CoV-2 infection itself.12 Social determinants
of health, including access to health care resources, endemic dis-
crimination, and education level, may also place vulnerable indi-
viduals at risk for post–COVID-19 neuropsychiatric sequelae.51
Gaps in Knowledge
Variable Disease Definitions
Variable follow-up periods and heterogeneous grouping of neuro-
psychiatric symptoms and disorders in existing COVID-19 literature
make it challenging to estimate the population at risk and the breadth
of resources necessary to address current and future burdens of ill-
ness. The conflation of subjective symptoms, diagnosed syn-
dromes, and objective testing abnormalities has muddied the un-
derstanding of PASC epidemiology. Short clinical observation times
related to the rapid emergence of SARS-CoV-2 may in part explain
the difficulties in producing a pragmatic working definition of PASC.
Iterative refinement of the defining features of PASC are expected
as biological mechanisms become better understood.
Lack of Biomarkers
Even when an association between SARS-CoV-2 and neuropsychi-
atric disease seems plausible, causality is difficult to verify without
pathological evidence or robust biomarker data. While active re-
search is ongoing internationally, there are no diagnostic criteria avail-
able to definitively identify SARS-CoV-2 as the underlying etiology
of either acute or postacute neuropsychiatric events.
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 Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19 Special Communication Clinical Review & Education

Table 2. Tiers of Neuropsychiatric Testing in the RECOVER Initiative Adult Clinical Protocola

Neurological testing Psychiatric testing Interval

Tier 1
Demographics Demographics Once, on enrollment
Social determinants Social determinants At infection/enrollment and
every 3 mo thereafter
Baseline disability Baseline disability Once, on enrollment
COVID-19 diagnosis, treatments, and vaccination status COVID-19 diagnosis, treatments, and vaccination status Once, on enrollment
Neurologic comorbidities Psychiatric comorbidities At infection/enrollment and
every 3 mo thereafter
Medications Medications At infection/enrollment and
every 3 mo thereafter
Symptoms: overall health status, physical function, fatigue, Symptoms: Anxiety (GAD2 to GAD7), depression (PHQ2 At infection/enrollment and
postexertional malaise, weakness in limbs, anosmia/dysgeusia, pain, to PHQ9), stress (PSS-4), trauma exposure and Primary every 3 mo thereafter
headache, neuropathy/myopathy, problems thinking or concentrating, Care PTSD screen, exposure to death/loss and grief,
sleep, dysautonomia, vision, hearing sleep, fatigue, concentration, alcohol and substance use
(NIDA TAPS tool), global mental health (in PROMIS 10)
Clinical assessment: 30-second sit to stand, active standing test, See tier 2 At and 6 mo after infection/
wearable device for sleep fragmentation, actigraphy enrollment, then yearly
Laboratory data Laboratory data At and 6 mo after infection/
enrollment, then yearly if
abnormal
Tier 2
Home sleep test, neurological examination, rehabilitation examination, Mini International Neuropsychiatric Interview, Columbia Once per year, maximum of 4
vision screen, smell test, NIH toolbox (oral reading recognition test, Suicide Severity Rating Scale, PTSD Checklist for DSM-5, times, if specific assessments
picture vocabulary test, auditory verbal learning test, inhibitory control Prolonged Grief 13 indicated by tier 1 measures
and attention test, pattern comparison processing speed test, picture
sequence)
Tier 3
Complete neurocognitive testing, complete eye examination with optical MRI brain ± gadolinium Once
coherence tomography, facility sleep study, audiometry, tilt table testing,
supine and upright catecholamine testing, single molecule array (tau,
neurofilament light), MRI brain ± gadolinium, EMG/NCS, skin and muscle
biopsy, lumbar puncture
Abbreviations: EMG/NCS, electromyogram/nerve conduction study; PROMIS, Patient-Reported Outcomes Measurement Information System;
GAD, General Anxiety Disorder measure; MRI, magnetic resonance imaging; PSS-4, Perceived Stress Scale 4; RECOVER, Researching COVID to Enhance
NIDA TAPS tool, National Institute on Drug Use screening tool for tobacco, Recovery initiative.
alcohol, prescription medication, and other substance use; NIH, National a
For more details on metrics, please visit the RECOVER site.1
Institutes of Health; PHQ, Patient Health Questionnaire;

SARS-CoV-2 Variants mechanisms, and identify therapeutic targets. Pre–COVID-19 cogni-

Genetic variants of SARS-CoV-2 may have different neurotropic and
secondary effects. Grouping together populations affected by dif-
ferent strains of SARS-CoV-2 may lead to difficulties in estimating
risk, causality, and outcome trajectories. Limited global genotyp-
ing makes subphenotyping difficult, beyond consideration of data
collection time frames and geographical trends.
Ascertainment Bias
Most epidemiologic data are not from the entire population at risk
and may underestimate rates of neuropsychiatric PASC among
populations with limited access to health care. Without a national
disease screening system, calculating observed rates in relation to
background expected neuropsychiatric event rates following SARS-
CoV-2 infection presents a challenge.
Lack of Longitudinal Studies
While there are multiple cohort studies and some ongoing longitudi-
nal studies of PASC among hospitalized patients, there is a relative
dearthofdataaddressingPASCamongthosewithasymptomatic,mild,
or moderate COVID-19. This may be due in part to the logistical chal-
lenges of conducting research outside the hospital setting during
pandemic lockdowns. Additionally, much of the current PASC litera-
ture contains stochastic or cross-sectional data. Repeated observa-
tions over time are needed to chart outcome trajectories, understand
tive, psychiatric, and functional status is often unknown or unre-
ported, making disentangling relapses or progression of underlying
disease processes vs de novo illness challenging.
Accounting for Social Determinants of Health
Health care disparities in the acute and chronic phases of COVID-19
have been well documented among different racial and socioeco-
nomic groups.51 Factoring pandemic-related stressors and social de-
terminants of health into PASC research is imperative for tailoring
population-level interventions.
Adequate Control Groups
While some studies have compared COVID-19 patients and those
with other infections, few include well-characterized contempora-
neous control groups. Age, sex, social determinants of health, and
comorbidity-matched control patients who are SARS-CoV-2 nega-
tive, as well as patients positive for SARS-CoV-2 who do not have pro-
longed symptoms, are needed to adequately characterize PASC.
Differences Across the Life Span
Some but not all studies identify older age as a risk factor for more se-
vereCOVID-19andPASC.12 However,asidefromstudiesaddressingmul-
tisystem inflammatory syndrome in children, there is a paucity of data
on neuropsychiatric effects of SARS-CoV-2 in children, neonates, and

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 Clinical Review & Education Special Communication Diagnosis and Management of Neuropsychiatric Sequelae of COVID-19

pregnant individuals. The effect of SARS-CoV-2 infection vs pandemic-
related factors on the developing brain may not be fully understood for
several years.
Effect of Treatments
Understanding the potential role of interventions for COVID-19 as
well as new or preexisting neurologic and psychiatric treatments is
also needed to fully recognize the contributors to neuropsychiatric
PASC.
Bridging Gaps
The RECOVER initiative is a NIH-funded multipronged approach to un-
derstanding PASC, which will address many of the aforementioned
knowledge gaps. RECOVER includes clinical cohort studies spanning
the age spectrum (adult, pediatric, pregnant populations), pathology
studies, and big data studies that draw from electronic medical rec-
ords. The adult clinical cohort study assesses disorders affecting mul-
tiple organ systems and is an ambidirectional, longitudinal meta-
cohortstudycombiningretrospectiveandprospectivedatawithnested
case-controlstudies.Thestudywillenroll15 000individualswithcases
that meet WHO criteria for suspected, probable, or confirmed SARS-
CoV-2 infection on or after March 1, 2020, as well as 2680 uninfected
control patients recruited from inpatient, outpatient, and community-
based settings, assuming a 25% rate of PASC among cases. The pri-
mary aims of RECOVER are to (1) characterize the incidence and preva-
lence of long-term sequelae of COVID-19 and describe subphenotypes,
(2) characterize the clinical course and recovery trajectories of PASC
and identify risk factors, and (3) identify mechanisms and pathophysi-
ology leading to PASC and potential modifiers.
RECOVER takes a 3-tiered approach to prospective data collec-
tion, with assessments from early tiers setting gateways for later-tier
testing across a broad range of potentially affected organ systems (eg,
cardiology,respiratory,neurologic,andpsychiatric1).Anestimated30%
of patients in tier 1 will go on to tier 2, and 20% will go on to tier 3 test-
ing for any given symptom. For example, a participant with a positive
tier 1 self-report screening measure for a psychiatric condition such as
depression, generalized anxiety disorder, or PTSD is referred to tier 2
structured clinical interview, while a subset who complete tier 2 with
confirmed psychiatric diagnoses are referred to magnetic resonance
imaging, which is tier 3 (Table 2). A proportion of uninfected partici-
pants and infected participants without relevant symptoms will also
complete tiers 2 and 3 as part of a control group. RECOVER does not
set a time frame from SARS-CoV-2 infection to symptom onset, nor a
symptom duration to qualify as PASC, because a primary aim is to de-
termine a data-based, practical definition using comparator groups.
RECOVER data will be accessible for researchers interested in con-
ducting ancillary studies, and RECOVER is expected to help identify
targets for future interventional trials.
Conclusions
Growing data support a high prevalence of PASC neuropsychiatric
symptoms, but the current literature is heterogeneous with vari-
able assessments of critical epidemiological factors. By enrolling
large, diverse patient samples across the age spectrum with vary-
ing levels of illness exposure and experiences, and conducting state-
of-the-art assessments, RECOVER will help clarify PASC epidemiol-
ogy, pathophysiology, and mechanisms of injury, as well as identify
targets for therapeutic intervention.

ARTICLE INFORMATION
Accepted for Publication: May 2, 2022.
Published Online: June 29, 2022.
doi:10.1001/jamapsychiatry.2022.1616
Author Contributions: Drs Frontera and Simon had
full access to all of the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Both authors.
Acquisition, analysis, or interpretation of data:
Both authors.
Drafting of the manuscript: Both authors.
Critical revision of the manuscript for important
intellectual content: Both authors.
Administrative, technical, or material support: Frontera.
Conflict of Interest Disclosures: Dr Frontera
reported grants from the National Institutes of
Health (NIH), consulting support from FirstKind and
Braincool, publishing fees from Thieme, and
speaking fees from Physician Education Resource
(PER) outside the submitted work. Dr Simon
reported grants from the NIH during the conduct of
the study; grants from the NIH, Patient-Centered
Outcomes Research Institute, Department of
Defense, American Foundation for Suicide
Prevention, Cohen Veterans Network, and Vanda
Pharmaceuticals; consulting fees from Vanda
Pharmaceuticals, Bionomics Limited, BehavR LLC,
Praxis Therapeutics, Cerevel, Genomind, and
Engrail Therapeutics; spousal equity in G1
Therapeutics and Zentalis; and royalties or fees
from APA Publishing, Wolters Kluwer (UpToDate),
and Wiley (Deputy Editor, Depression and Anxiety)
outside the submitted work. No other disclosures
were reported.
Funding/Support: Both authors receive funding as
co-investigators/faculty at the NYU Grossman
School of Medicine for the RECOVER initiative
(OTA-21-015A Post-Acute Sequelae of SARS-CoV-2
Infection Initiative: NYU Langone Health Clinical
Science Core). Dr Frontera receives funding for the
following COVID-19–related grants from these NIH
institutes: National Institute of Neurological
Disorders and Stroke (3U24NS11384401S1),
National Heart, Lung, and Blood Institute
(1OT2HL161847-01), and National Institute on Aging
(3P30AG066512-01).
Role of the Funder/Sponsor: The funding
organization had no role in the preparation, review,
or approval of the manuscript or decision to submit
the manuscript for publication.
Additional Information: There was no original data
collection or analyses for this Special
Communication.
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